Asthma is a chronic lung disease affecting millions of people. It is thought to involve three major factors: swelling of the airways, constriction of the muscles around the airways and inflammation. Symptoms of asthma differ widely among sufferers. While some people experience tightness of the chest, wheezing, and difficulty breathing only intermittently, (e.g., with exercise), others experience these symptoms daily.
The precise cause of asthma is not known, but genetic predisposition appears to be an important factor. The most typical triggers of asthma attacks are cold air, exercise, infection, common viruses, irritants, and allergens (e.g., pollen, pet dander, etc.). When the airways come in contact with one of these triggers, the tissue inside the bronchi and bronchioles becomes inflammed and the muscles on the outside of the airways constrict, causing them to narrow. Mucus enters the airways, causing them to swell, and narrow further. Sometimes avoiding the trigger is all that is necessary to prevent an asthma attack. However, avoiding asthma triggers in all instances is seldom possible, so asthma typically requires medical treatment.
There are two primary types of medicines used to treat asthma: the “relievers” and the “controllers” (sometimes also referred to as the “preventers”). Reliever medicines are typically bronchodilators. They are used to provide immediate relief of asthma symptoms (e.g., wheezing, coughing, tightness in the chest, shortness of breath, etc.). Bronchodilators function by dilating, or opening up, the bronchi (i.e., the larger airways delivering air inside the lungs). Most commonly prescribed are the β2-adrenoceptor agonists, also referred to as the β-adrenergics (e.g., epinephrine, isoproterenol, albuterol, salmeterol, salbutamol, terbutaline, isoprenaline, isoetharine, metaproterenol, etc.) and the xanthines (e.g., caffeine, theophylline, etc.).
Controllers or preventers, on the other hand, are typically anti-inflammatory medicines. They are medicines taken on a regular basis, even when the asthmatic is not suffering from any symptoms. The goal of these medicines is to prevent asthma symptoms from developing. Controllers function by decreasing the inflammation (e.g., fluid and cellular debris) inside the airways. They are divided into several classes of medications, the most common of which are the corticosteriods. Mediator-release inhibitors and leukotriene modifier agents are also anti-inflammatories used to control asthma. These medicines may also be useful in treating certain respiratory diseases or ailments.
Beyond asthma, other common and/or important respiratory diseases include chronic obstructive pulmonary disease, pulmonary fibrosis (most notably idiopathic pulmonary fibrosis), pulmonary hypertension, and cystic fibrosis. Many of these diseases, especially chronic obstructive pulmonary disease, may be improved by the medications described above for use in asthma.
Chronic obstructive pulmonary disease (COPD) is a common and serious disease strongly associated with cigarette smoking and characterized by chronic productive cough or abnormal permanent enlargement of the alveolar (deep lung) airspaces, accompanied by difficulty moving air in and out of the lungs. This difficulty moving air results shortness of breath on exertion and expiratory wheezes or decreased breath sounds on chest examination. The disease is generally progressive, with severe blood oxygen deficiency and carbon dioxide overload occurring in the late stages. Despite the serious and progressive nature of the underlying pathology of COPD, the disease also frequently involves an airway hyperreactivity (asthma-like) component that may be reversible, resulting in the total obstruction to airflow being partially reversible. COPD is thus sometimes hard to differentiate from unremitting asthma, and the asthma treatments described above are among of the most important treatments for COPD.
Pulmonary fibrosis generally involves chronic inflammation of the alveolar walls with progressive fibrosis. Clinical manifestations include shortness of breath on exertion, nonproductive cough, crackles on chest examination, and, at later stages, digital clubbing and cyanosis. Pulmonary hypertension is an obliterative disease of medium and small pulmonary arteries resulting in heart failure. The key clinical manifestation is progressive exertional shortness of breath. Both of the above diseases have very poor prognosis, frequently resulting in death within 2 to 7 years of diagnosis. Nevertheless, certain respiratory agents, such as anti-endothelin drugs and prostacyclin drugs, provide some survival and/or quality of life benefits.
Cystic fibrosis is an inherited disease of secretory glands, affecting multiple body organs, with a strong respiratory component. It is the most common life-shortening genetic disease in the U.S., and is caused by a genetic defect in a particular chloride-transporting protein, the cystic fibrosis transmembrane regulator. Its respiratory symptoms generally include those of chronic pulmonary obstruction. Beyond the treatments described above, which may be effective in treating the obstructive pulmonary symptoms of cystic fibrosis, other treatments may also be useful, in particular ion channel or pump inhibitors, enhancers, or modulators.
While agents for the treatment of respiratory disease may be delivered by many routes, including systemic routes, many agents effective for the treatment of respiratory disease, e.g., relievers and controllers, are delivered in aerosol form via inhalers. Currently, there are three basic types of inhalers available: nebulizers (jet and ultrasonic), metered dose inhalers, (“MDIs,” including MDIs with spacers), and dry powder inhalers (“DPIs”). These inhalers are used for both aerosol generation and aerosol delivery of asthma drugs.
Nebulizers aerosolize liquids and produce a mist of drug-containing water particles for inhalation. There are two basic types of nebulizers, the jet nebulizer, and the ultrasonic nebulizer. Jet nebulizers are more common than ultrasonic nebulizers, because they are less expensive. Typically, with a jet nebulizer, compressed gas flows from an inlet tube over the top of a tube whose end is immersed in a drug solution. The venturi effect creates a pressure drop, which sucks up the liquid and causes it to enter the air stream where it is rapidly dispersed into droplets. The stream of air and water droplets is directed against a baffle, which breaks the droplets into small particles. The small particles are then carried out of the nebulizer suspended in air, and the remaining droplets re-enter the solution. With ultrasonic nebulizers, particles are produced by mechanical vibration of a plate or mesh using a piezoelectric crystal.
With MDIs, a measured (i.e., metered) dose of medicine is dispensed into the user's mouth using a small amount of pressurized gas (i.e., a propellant). Sometimes a spacer is placed between the drug reservoir and the user's mouth in order to control the amount of aerosol that is inhaled. The aerosol of a MDI is created when a valve is opened (usually by pressing down on a propellant canister), allowing liquid propellant to spray out by cavitation. The drug is usually contained in small particles suspended in the liquid propellant, but in some formulations the drug is dissolved in the propellant. In either case, the propellant evaporates rapidly as the aerosol leaves the device, resulting in small drug particles that are inhaled. Prior to the mid 1990s, MDIs used various chlorofluorocarbons (“CFCs”) as their propellant, but with the elimination of CFCs in industry due to ozone depletion concerns, the propellants in new MDIs typically use hydrofluoroalkanes (“HFAs”).
Unlike the aerosols discussed above, the aerosols produced by DPIs are in the form of a powder. Typically the asthma drugs of DPIs are manufactured in powder form as small powder particles of a few micrometers in diameter. The asthma drug is then typically mixed with larger sugar particles, for example, lactose monohydrate, (e.g., typically 50-100 micrometers in diameter). The asthma drug particles attach to the excipient lactose particles. The increased aerodynamic forces on the lactose/drug agglomerates are thought to improve entrainment of the small drug particles upon inhalation. Upon inhalation, the powder is broken into its constituent particles with the aid of turbulence and, in some instances, mechanical devices such as screens or spinning surfaces. Dry powder formulations, while offering advantages over the cumbersome liquid nebulizer formulations, and the propellant-driven formulations, are prone to aggregation and low flowability phenomena which considerably diminish the efficiency of the dry powder-based inhalation therapies.
Despite the variety of inhalation devices available, these devices are suboptimal in numerous respects. For example, MDIs need to be shaken prior to use. Many users fail to shake the MDIs and therefore receive inconsistent amounts of medication. Other times, the MDI ejects the drug with such a great exit velocity or in such a large particle size that the drug collides with the back of the throat and does not reach the lung in substantial quantity. For nebulizers, undesirably large particle size is also a common problem, as is slow aerosolization of the drug. Because of slow aerosol generation, nebulizer treatments often require a patient to inhale on the nebulizer for minutes to hours to receive a therapeutic amount of medication, disrupting the patient's other life activities or providing unacceptably slow relief of an acute asthma attack. Another problem with liquid inhalers such as nebulizers is that delivery of liquids other than neutral pH saline to the lungs may irritate the lungs, whereas saline may provide a vehicle that carries bacteria or other pathogens into the lungs. Also, many important drugs are not soluble in neutral pH saline. For dry powder inhalers, undesirably large particle size is again a problem. The problem is particularly severe for patients who cannot inhale with much vigor, because vigorous inhalation is generally required to disperse the powder. Because respiratory patients in need of inhaled medications frequently have impaired abilities to inhale, the above problem of strong inhalation being required to disperse dry powders is particularly clinically significant. Another problem with dry powders is that they contain additives such as lactose, generally in quantities exceeding the quantity of drug in the inhaler. Such additives may irritate or otherwise damage the lung, while providing no therapeutic benefits.
Accordingly, it would be desirable to provide improved respiratory drug aerosols and improved inhalation devices for administering such aerosols.